Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

  • Christineh N. Sarkissian
  • Alejandra Gamez
  • Patrick Scott
  • Jerome Dauvillier
  • Alejandro Dorenbaum
  • Charles R. Scriver
  • Raymond C. Stevens
Research Report
Part of the JIMD Reports book series (JIMD, volume 5)


Prospectively enrolled phenylketonuria patients (n=485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN®). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5–20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.



We are indebted to the PKU patients and families who enrolled this study, as well as doctors and their healthcare staff for their invaluable assistance in the conduct of the clinical studies. We also thank our colleagues, John Tomaro for data collection, Sonia Schnieper-Samec for help with statistical review, Kumar Saikatendu and Katya Kadyshevskaya for the 3D figure preparation, Angela Walker for assistance with manuscript preparation and submission to the journal, Sun Sook Kim and Sabrina Cheng for data revision, and Manyphong Phommarinh and Jacques Mao for assistance with PAHdb. A. Gamez was supported by a research contract from “Ramón y Cajal” program by Ministerio de Ciencia e Innovación and Fundación Ramón Areces.

Supplementary material

Suppl table 1.xls (130 KB)

Suppl table 2.doc (18 KB)

Suppl table 2.doc (98 KB)


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Christineh N. Sarkissian
    • 1
    • 2
  • Alejandra Gamez
    • 3
  • Patrick Scott
    • 1
  • Jerome Dauvillier
    • 4
  • Alejandro Dorenbaum
    • 5
  • Charles R. Scriver
    • 1
    • 2
  • Raymond C. Stevens
    • 6
  1. 1.Departments of Biology, Human Genetics and PediatricsMcGill UniversityMontrealCanada
  2. 2.Debelle LaboratoryMcGill University-Montreal Children’s Hospital Research InstituteMontrealCanada
  3. 3.Centro de Biología Molecular Severo Ochoa, Nicolas Cabrera 1 Laboratorio 204. Campus CantoblancoUniversidad Autónoma de MadridMadridSpain
  4. 4.Merck Serono S.AGenevaSwitzerland
  5. 5.BioMarin Pharmaceutical IncNovatoUSA
  6. 6.Department of Molecular BiologyThe Scripps Research InstituteLa JollaUSA

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